Although hematopoietic tumors such as leukemia are first treated by chemotherapy with anticancer agents, patients who are difficult to cure or less likely to be cured with standard chemotherapy further require transplantation of hematopoietic stem cells (e.g., peripheral blood stem cells, bone marrow cells). However, it is pointed out that transplantation of hematopoietic stem cells will cause graft-versus-host disease (GVHD).
GVHD is a generic name for diseases that are caused by the immune reaction of transferred or transplanted immunocompetent cells against host tissues. This would be mainly because immunocompetent cells (e.g., mature T cells) contained in peripheral blood to be transferred or transplanted will cause immune responses against recipient tissues. GVHD includes both acute and chronic types of diseases with symptoms such as skin symptoms, diarrhea and icterus, which can develop a severe effect leading to death in some cases.
Techniques conventionally used to suppress GVHD include those based on the use of immunosuppressive agents such as methotrexate or cyclosporin A, as well as those based on the removal of mature T cells from a group of transplant cells (graft). In the case of using methotrexate or cyclosporin A, a problem arises from their side effects on the body. Cyclosporin A is known to have a strong nephrotoxicity as a side effect, while methotrexate is known to cause bone marrow suppression as a side effect.
On the other hand, the removal of mature T cells from a group of transplant cells allows suppression of GVHD, but it has a drawback in that the antitumor effect becomes attenuated leading to, e.g., leukemia relapse (Non-patent Document 1).
Interleukin 6 (IL-6) is a cytokine called B cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in activation of B cell lymphocytes (Non-patent Document 2), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-patent Document 3). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-patent Document 4).
IL-6 transmits its biological activity via two kinds of proteins on the cell. The first kind of protein is IL-6 receptor, which is a ligand-binding protein to which IL-6 binds; it has a molecular weight of about 80 kDa (Non-patent Documents 5 and 6). The IL-6 receptor is present in a membrane-bound form that penetrates and is expressed on the cell membrane, and also as a soluble IL-6 receptor, which mainly consists of the extracellular region of the membrane-bound form.
The other kind of protein is the membrane protein gp130, which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of an IL-6/IL-6 receptor complex from IL-6 and IL-6 receptor followed by binding of the complex with gp130 (Non-patent Document 7).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Currently, known IL-6 inhibitors include antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptor (anti-IL-6 receptor antibodies), antibodies against gp130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptor, and such.
There are several reports regarding anti-IL-6 receptor antibodies (Non-patent Documents 8 and 9, Patent Documents 1 to 3). One such report details a humanized PM-1 antibody, which is obtained by grafting the complementarity determining region (CDR) of mouse antibody PM-1 (Non-patent Document 10), which is an anti-IL-6 receptor antibody, into a human antibody (Patent Document 4).
Antibodies against IL-6 receptor are used for treatment of inflammatory diseases such as rheumatism. However, inflammatory cytokines including IL-6 form a complex network, and hence it has been unclear whether IL-6 receptor inhibitors are effective for treatment of other diseases such as graft-versus-host disease.
In fact, it has been reported that no therapeutic effect was obtained in IL-6-expressing GVHD model mice even when administered with anti-IL-6 antibody (Non-patent Document 11).
Prior-art documents relevant to the present invention will be shown below.    Non-patent Document 1: Marmont, A M. Et al., Blood (1991) 78, 2120-2123    Non-patent Document 2: Hirano, T. et al., Nature (1986) 324, 73-76    Non-patent Document 3: Akira, S. et al., Adv. in Immunology (1993) 54, 1-78    Non-patent Document 4: Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258    Non-patent Document 5: Taga, T. et al., J. Exp. Med. (1987) 166, 967-981    Non-patent Document 6: Yamasaki, K. et al., Science (1988) 241, 825-828    Non-patent Document 7: Taga, T. et al., Cell (1989) 58, 573-581    Non-patent Document 8: Novick, D. et al., Hybridoma (1991) 10, 137-146    Non-patent Document 9: Huang, Y. W. et al., Hybridoma (1993) 12, 621-630    Non-patent Document 10: Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906    Non-patent Document 11: Knulst A. C. et al., Mediators of Inflammation (1994) 3, 33-40    Patent Document 1: International Patent Publication No. WO 95/09873    Patent Document 2: French Patent Publication No. FR 2694767    Patent Document 3: U.S. Pat. No. 5,216,128    Patent Document 4: International Patent Publication No. WO 92/19759